Management of Relapsed Multiple Myeloma: Recommendations of the International Myeloma Working Group

Journal Club Library published on December 12, 2016

Laubach J, Garderet L, Mahindra A, et al. Leukemia. 2016;30(5):1005-1017.

Article summary written by Patrick Brooks, PharmD, Medical Director, Oncology

Multiple myeloma (MM) is an incurable B-cell neoplasm, and patients will ultimately relapse, even if they achieve prolonged, high-quality responses to initial therapy. However, new definitions of relapse, which support treatment of patients with asymptomatic disease based on biochemical changes, and the approval of new therapies in the relapsed/refractory setting, may provide more options and new hope for patients with relapsed/refractory multiple myeloma (RRMM). In December of 2015, the International Myeloma Working Group (IMWG) published recommendations for assessing and treating relapsed disease based on these new developments.1

Progressive MM is defined as 25% increase from baseline in:

  • Serum monoclonal protein (M-protein; absolute increase ≥0.5 g/dL), and/or
  • Urine M-protein (absolute increase >200 mg/day), and/or
  • Percentage of bone marrow plasma cells (absolute increase >10%), and/or
  • Difference between involved and uninvolved free light chain levels (absolute increase >10 mg/dL)

Progressive MM is also defined by the presence of new bone lesions and/or soft tissue plasmacytomas, with a clear increase in the size of existing plasmacytomas, or hypercalcemia that cannot be attributed to another cause.

A thorough evaluation of relapsed disease includes the following:

  • Serum protein electrophoresis (SPEP) with immunofixation
  • 24-hour for both total protein and urine protein electrophoresis (UPEP) with immunofixation
  • Serum-free light chain (SFLC) assay
  • Metabolic panel (focusing on renal function, calcium levels and other metabolic abnormalities)
  • Complete blood count (CBC) with differential
  • β2 microglobulin levels
  • Bone marrow evaluation (may be omitted if disease progression is clearly confirmed by SPEP/UPEP and/or SFLC assay)
  • Fluorescence in situ hybridization (FISH) to detect new chromosomal abnormalities (may be omitted in cases where high-risk cytogenetics were previously identified)
  • Imaging via skeletal survey, magnetic resonance imaging (MRI), or fluorodeoxyglucose-positron emission tomography (FDG-PET)

Patients should initiate treatment for relapsed disease when they are symptomatic, experience a rapidly increasing M-protein level, or have extramedullary disease; a doubling of the M-spike within 3 months indicates a rapid relapse, and therapy should be initiated. However, patients who experience asymptomatic biochemical relapse and a slow rise in M-protein level should be restaged and followed-up with every 3 months. It is important to note that transient oligoclonal reconstitution can occur after autologous stem cell transplant (ASCT), and should not be treated.

Guidelines for the Treatment of RRMM

  • Patients who are naïve to an agent (or drug class) are typically treated with a regimen incorporating this agent (or any agent from the drug class)
  • Patients who previously responded to an agent with a duration of response (DOR) of at least 6-9 months can be retreated at relapse with the same agent or in combination with other agents
  • Patients with high-risk disease without comorbidities and with adequate performance status should be treated with highly active three- or four-drug combinations; ASCT can be considered in select patients who respond
  • Patients with indolent disease should be treated with regimens that include an agent to which the patient is naïve or has known sensitivity; ASCT can be considered in patients without prior exposure to high-dose therapy and who responded to prior ASCT, as evidence by a progression-free survival (PFS) interval of ≥18 months following transplant
  • Patients eligible for a second ASCT should have had stem cells collected prior to the first ASCT, or a new collection must be done; this can be achieved through stem cell mobilization with granulocyte colony stimulating factor (G-CSF) only, cyclophosphamide plus G-CSF, or plerixafor, after reinduction
  • Patients younger than 65-70 years may be eligible for allogeneic stem cell transplant (allo-SCT), but the impact on overall survival is controversial; allo-SCT is often used as a last option when other approaches are no longer effective
  • Patients being treated for second relapse and beyond should be offered participation in a clinical trial, if available, or treated with a salvage regimen incorporating at least one agent to which there has not been prior evidence of resistance or intolerability; treat patients until the regimen is no longer tolerated or there is evidence of disease progression, then switch to an alternative regimen

These recommendations by the IMWG serve as guidelines to help health care providers navigate the complex treatment paradigms for RRMM. While these recommendations are still valid today, it is important to note that a number of new therapies have become available, including the oral proteasome inhibitor ixazomib, and the monoclonal antibodies elotuzumab and daratumumab. The National Comprehensive Cancer Network (NCCN) updated their practice guidelines in October of 2016, with the following recommended treatment options for RRMM2:

As the assessment, treatment, and management of relapsed/refractory multiple myeloma continues to evolve, it is important for health care providers to remain steadfast in consulting the latest clinical evidence and recommendations to ensure their patients are being treated optimally, while exercising clinical judgement in all of their health care decisions on a case-by-case scenario.


  1. Laubach J, Garderet L, Mahindra A, et al. Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group. Leukemia. 2016;30(5):1005-1017.
  2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 2.2017. Accessed at on November 28, 2016.
Last modified: December 6, 2016